title: The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients.
  
  
  RESULTS
  HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DL(CO)) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036).
  
  
  CONCLUSIONS
  DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xue
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
authors.forename: Ahmad Samer
authors.initials: AS
authors.lastname: Alawad
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
authors.forename: Imre
authors.initials: I
authors.lastname: Noth
authors.forename: Steven D
authors.initials: SD
authors.lastname: Nathan
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Rosen
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.forename: Sanja
authors.initials: S
authors.lastname: Dacic
authors.forename: Iclal
authors.initials: I
authors.lastname: Ocak
authors.forename: Carl R
authors.initials: CR
authors.lastname: Fuhrman
authors.forename: Karen T
authors.initials: KT
authors.lastname: Cuenco
authors.forename: Mary A
authors.initials: MA
authors.lastname: Smith
authors.forename: Susan S
authors.initials: SS
authors.lastname: Jacobs
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Morel
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pilewski
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Valentine
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Frank C
authors.initials: FC
authors.lastname: Sciurba
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Steven R
authors.initials: SR
authors.lastname: Duncan
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015995:Prevalence
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D000949:Histocompatibility Antigens Class II